Project Summary The proposed project aims to fundamentally advance the ENCODE Consortium's catalog of functional sequence elements in the human genome. ENCODE has already established a seminal resource that is enabling human biology, genetics and disease research. However, progress towards the Consortium's goal of identifying all functional genomic elements has been constrained by modest assay throughput and by the fact that functional elements tend to be exquisitely context-specific, only declaring themselves in specific developmental intervals, in specific disease settings, or in specific cell types obscured by tissue heterogeneity. To overcome these limitations and hasten progress towards ENCODE goals, the proposed project will purify highly specialized cell types from normal human tissues and blood, from tumors and other disease specimens, and from laboratory 'organoid' models that faithfully recapitulate developing brain, kidney or gut. These purified cell types will be applied to a multiplexed pipeline capable of acquiring genome-wide chromatin state maps with unprecedented throughput and low cost. Thousands of maps reflecting different chromatin modifications in different cell types will be integrated to derive a comprehensive set of sequence elements in the human genome, annotated by their predicted functions and cell type-specificities. The project will bring together a diverse team of experts in human biology and development, chromatin biology, genomics, and production research. This scientific team will coordinate closely with other Data Production, Coordination, Analysis and Functional Characterization Centers in the Encode Consortium to assemble a common catalog of the locations and cell type-specific functions of regulatory elements in the human genome. These annotations, and all primary data collected in the project, will be made freely available to the scientific community, with the goal to catalyze biomedical research and advance genomic medicine.